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. 2021 May 7;13(9):2095-2116.
doi: 10.1002/cctc.202001886. Epub 2021 Jan 28.

Biosynthetic Cyclization Catalysts for the Assembly of Peptide and Polyketide Natural Products

Maria L Adrover-Castellano  1 , Jennifer J Schmidt  1 , David H Sherman  1
Affiliations

Biosynthetic Cyclization Catalysts for the Assembly of Peptide and Polyketide Natural Products

Maria L Adrover-Castellano et al. ChemCatChem. .

Abstract

Many biologically active natural products are synthesized by nonribosomal peptide synthetases (NRPSs), polyketide synthases (PKSs) and their hybrids. These megasynthetases contain modules possessing distinct catalytic domains that allow for substrate initiation, chain extension, processing and termination. At the end of a module, a terminal domain, usually a thioesterase (TE), is responsible for catalyzing the release of the NRPS or PKS as a linear or cyclized product. In this review, we address the general cyclization mechanism of the TE domain, including oligomerization and the fungal C-C bond forming Claisen-like cyclases (CLCs). Additionally, we include examples of cyclization catalysts acting within or at the end of a module. Furthermore, condensation-like (CT) domains, terminal reductase (R) domains, reductase-like domains that catalyze Dieckmann condensation (RD), thioesterase-like Dieckmann cyclases, trans-acting TEs from the penicillin binding protein (PBP) enzyme family, product template (PT) domains and others will also be reviewed. The studies summarized here highlight the remarkable diversity of NRPS and PKS cyclization catalysts for the production of biologically relevant, complex cyclic natural products and related compounds.

Keywords: Biocatalysis; Enzymes; Natural Products; Nonribosomal Peptide Synthetase; Polyketide Synthase.

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Figures

Figure 1.
Figure 1.
NRPS and PKS domains including the cyclization and release domains discussed throughout this review.
Figure 2.
Figure 2.
Overall structure of PKS and NRPS thioesterases with the core α - helices depicted in teal, the lid α-helices depicted in yellow, β strands represented in purple. a. Topology diagram of TEs with the catalytic residues highlighted. b. Representation of PikTE (PDB: 2H7X) highlighting the substrate channel typically seen in PKS TEs and a triketide substrate seen in pink. c. Representation of VlmTE (PDB: 6ECE) depicting the buried, bowl shaped active site with the lid forming the top cap.
Figure 3.
Figure 3.
Mechanism of the lactonization or hydrolysis of a CP-tethered peptide or polyketide intermediate. Highlighted in green throughout the review, the bond formed via the described enzyme.
Figure 4.
Figure 4.
Chemical structures of the lactones pikromycin, erythromycin, obafluorin, salinamide A and lysobactin.
Figure 5.
Figure 5.
Chemical structures of the lactams sulfazecin, polymyxin B and fluvirucin B1.
Figure 6
Figure 6
a. Chemical structures of cryptophycin analogs, teixobactin, zearalenone and radicicol. b. In vitro biocatalytic platform using the terminal two monomodules (PikAIII and PikAIV) of the pikromycin pathway.
Figure 7
Figure 7
a. Engineering of the Pik TE for synthesis of novel macrolactones. b. Chemical structures of cilengitide and the tautomycetin polyketide natural products.
Figure 8
Figure 8
a. Chemical structures of cereulide, valinomycin and elaiophylin. b. Proposed mechanism for TE oligomerization in conglobatin biosynthesis.
Figure 9
Figure 9
a. WA TE/CLC mechanism for the production of YWA1. b. PksA TE/CLC domain catalyzes the Claisen cyclization (C-C bond formation) of noranthrone.
Figure 10
Figure 10
a. PhnA TE/CLC C1-C10 Claisen cyclization producing the naphthopyrone prephenalenone. b. Shunt products from the PhnA TE deletion (TE0).
Figure 11
Figure 11
a. CT cyclization routes. A and B represent two possible cyclization routes by the CT domain for the formation of fumiquinazoline F. b. Crystal structure of the holo T domain (gold) in conjunction with the CT domain (purple). The Ppant arm and the conserved histidine are drawn in pink. The salt bridge between E4019 (pink) of the β12 - β13 loop and R3652 (teal) of helix α2 is highlighted to show the closure of the solvent channel at the acceptor site.
Figure 12.
Figure 12.
Function of GliP and abbreviated biosynthesis of gliotoxin showing the most abundant intermediates or shunt metabolites (32) and (33), as well as the detoxification product (34).
Figure 13
Figure 13
a. Initial steps in the biosynthesis of nanangelenin A. b. Biosynthesis of benzomalvins proceeds through formation of the Anth-NmPhe dipeptide covalently bound via a thioester bond to the second T-domain of BenZ. BenZ-C2 subsequently catalyzes formation of the Anth-NmPhe-Anth tripeptide covalently bound to BenY-T. BenYCT then catalyzes cyclization and cleavage of the thioester bond, leading to trans-annulation and production of benzomalvin A/D.
Figure 14
Figure 14
a. Mutanobactins A – D. b. Reductase (R) domain mediated release of aldehyde precursor in the biosynthesis of mutanobactins.
Figure 15
Figure 15
a. Termination step mediated by the reductase (R) domain in the biosynthesis of koranimine B. b. Final step in the biosynthesis of lugdunin and nucleophilic attack of the cysteine thiol group forming the 5-membered thiazolidine heterocycle.
Figure 16.
Figure 16.
Structures of anthramycin, tomaymycin, tilivalline and tilimycin.
Figure 17.
Figure 17.
Dieckmann cyclization mediated by a reductase domain (RD) in the biosynthesis of tenellin.
Figure 18
Figure 18
a. RD domain in the biosynthesis of equisetin and fusaridione A. The activity of the RD domain results in release of the intermediate as the tetramate, trichosetin. Then, N-methylation is carried out to give equisetin. b. For the case of fusaridione A, the unstable pyrrolidinedione ring is opened through a reverse-Dieckmann reaction. c. Proposed biosynthetic pathway for burnettramic acids A and B.
Figure 19.
Figure 19.
Activity and structure of Dieckmann cyclases. a. Dieckmann cyclization reaction in the biosynthesis of five actinomycete-derived tetramic acid and pyridone natural products. b. NcmC-cerulenin complex with the α/β hydrolase subdomain highlighted in grey and the four-helix bundle in green. Catalytic residues important for function are depicted in blue and purple.
Figure 20
Figure 20
a. The fully elongated peptide chains tethered to the last NRPS modules are presumed to be released by SurE to generate cyclopeptides 61–65 and the linear peptide 66.[110] b. Overall Structure of SurE with PBP domain depicted in light grey for the apo form and dark grey for the complexed form, lipocalin like domain in cyan and the linker between the two in purple. Active site residues are depicted in blue with the density for the visible leucine in pink. The loop rearrangement is highlighted in green for the ordered apo form. c. Active site of SurE including comparison of loop region His225 and Met226 in apo (green) and complex structure with D-Leu (grey).
Figure 21.
Figure 21.
PT domain in the NR-PKS PksA for the biosynthesis of aflatoxin B1.
Figure 22.
Figure 22.
PT domain cyclization regioselectivities in NR-PKSs.
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